It is known that radiolabeled antibodies to carcinoembryonic antigen (CEA) can be used to localize tumors. U.S. Pat. No. 3,927,193, to Hansen et al, discloses such a method, but provides examples of its use only in animals. The method described in this patent does not explain how tumors may be visualized in a situation where radio-activity is also present in other sites of the body, such as blood, other body fluids and certain tissues, particularly heart and liver, which can prevent precise discrimination of the radioactivity associated with the sites of tumor. This reference also teaches that the anti-CEA antibody should not be labeled to a degree which might interfere with its specificity, a limitation which was not questioned in the later references discussed below. However, this limits the resolution of the method and requires larger quantities of antibody for image detection.
Early clinical studies reported by Reif et al, J. Surg. Oncol., 6, 133 (1974) and Mach et al, Europ. J. Cancer, Suppl. 1, 113 (1978) failed to show tumorlocalization in humans with radioactive anti-CEA antibodies.
Goldenberg et al, in an article in the New Engl. J. Med., 298, 1384 (1978), reported success in clinical trials of tumor detection and localization by scintillation scanning of patients receiving radiolabeled antibodies to CEA. In that reference, it was noted that there was a problem in both animal and human studies in distinguishing specific radioantibody activity from bloodpool background activity, and that special scanner subtraction techniques with other radionuclides were considered essential for unequivocal tumor localization using this method. The antibody preparation used in the reference was 70% immunoreactive with CEA. The reference further notes that the absence of CEA in normal hamster tissues precludes extrapolation to man, in whom the antigen usually circulates in increased levels in patients with cancer, and is present in lesser quantities in certain normal tissues. The subtraction technique used to permit localization using this scintigraphic method involved injection of Tc-99m-pertechnetate and Tc-99m-labeled human serum albumin prior to each imaging scan. The data obtained were stored in a minicomputer, capable of generating digital images of the labeled antibody alone, the Tc-99m labeled species together, and sums and differences of these various values. However, even this successful tumor localization and detection process had certain disadvantages which limited its resolution, its efficiency and its practicability. The subtraction technique involved the use of a different radionuclide attached to a carrier having kinetics of transport and distribution different from the labeled specific antibody. In addition, the background-compensating material had to be injected prior to each photoscan, which exposed the patient to increased levels of radioactivity and discomfort.
CEA is considered to be primarily a cell-surface antigen, as reported by Heyderman, Scand. J. Immunol., 8, Suppl. 8, 119 (1978), and many others. However, tumor localization using antibodies to cell surface antigens has hitherto been limited to anti-CEA antibodies. Related applications Ser. Nos. 126,261 and 126,263 (now U.S. Pat. No. 4,331,647), both filed Mar. 3, 1980, the disclosures of which are also incorporated herein by reference, disclose tumor localization with labeled antibodies to intracellular tumor associated antigens and with labeled antibody fragments specific to tumor associated markers, respectively.
Tumor radiotherapy using antibodies has been suggested by many, and an indication of its success in a single multimodal therapeutic clinical use was reported by Ettinger et al., Cancer Treat. Rep., 63, 131 (1979). The use of boron-labeled antibodies in therapy was reported by Hawthorne et al., J. Med. Chem., 15, 449 (1972), but the combined incorporation of boron and a radioisotope for localization and therapy was not suggested.
A need continues to exist for methods of tumor detection and localization using cell-surface antigens which are not confined to the use of antibodies to CEA, which do not require repeated injection of background-compensating material for a subtraction technique, which are adaptable to both diagnosis and therapy, which have high reliability and high resolution, which ideally are capable of detecting and locating more than one type of tumor or tumor cells using a single injection, and which avoid other disadvantages of the prior art methods.